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Diss Factsheets

Administrative data

Description of key information

Two studies were performed to assess the skin and eye irritancy potential of the 4,4'-Benzylidenedianiline in the New Zealand White rabbit, according to the OECD guidelines 404 and 405 and EC Regulation methods B4 and B5, accordingly.

None of the applications to the rabbit intact skin produced any evidence of skin irritation.

A single application of the test material to the non-irrigated eye of two rabbits produced moderate conjunctival irritation but treated eyes appeared normal at the 48-hour observation.

It can be concluded that 4,4'-Benzylidenedianiline is not irritant to the skin but mildly irritant for the eyes.

The test item is not classified according to CLP criteria for skin and eye irritation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
25 November 2009 - 04 December 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
24 April 2002
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
No. 440/2008
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
- Source of test material: Sponsor (identification DATIPH)
- Description: brown solid lumps 09 November 2009
- Date received: 09 November 2009
- Storage conditions: approximately 4°C in the dark

The integrity of supplied data relating to the identity, purity and stability of the test material is the responsibility of the Sponsor.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: For the purpose of the study the test material was ground to a powder prior to application.
- Preliminary purification step (if any):
- Final dilution of a dissolved solid, stock liquid or gel:
- Final preparation of a solid:

FORM AS APPLIED IN THE TEST (if different from that of starting material)

TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable)

OTHER SPECIFICS:
The absorption of the test material was not determined.
The pH of the test material was determined prior to commencement of the study and found to be as follows:

Preparation pH Measurement
immediately after 10 minutes after 20 minutes
10% w/w aqueous preparation of the test material 8.9 9.4 9.5

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Hillcrest, Belton, Loughborough, UK
- Age at study initiation: twelve to twenty weeks old
- Weight at study initiation: 2.38 or 2.39 kg
- Housing: individually housing in suspended cages
- Diet (e.g. ad libitum): 2030 Teklad Global Rabbit diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK
- Water (e.g. ad libitum): 2030 Teklad Global Rabbit diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK
The diet and drinking water were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Remarks:
On the day before the test each rabbit was clipped free of fur from the dorsal/flank area using veterinary clippers.
Vehicle:
water
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g of the test material, moistened sufficiently with 0.5 ml of distilled water to achieve a paste
Duration of treatment / exposure:
One animal with three patches for a duration of 3 minutes, 1 hour and 4 hours, respectively.
The second animal with one patch for 4 hours.
Observation period:
lmmediately following removal of the patches and approximately 1, 24, 48 and 72 hours later, the test sites were examined for evidence of primary irritation and scored according to the following scale. The proposed 24 and 48-hour observations at the 3 minute and 1- hour exposure sites were performed approximately three to four hours later than specified in the guideline.
Number of animals:
2
Details on study design:
TEST SITE
- Area of exposure: three suitable sites on the back of the rabbit
- % coverage: area under the 2.5 cm x 2.5 cm cotton gauze patch
- Type of wrap if used: the trunk of the rabbit was wrapped in an elasticated corset for the duration of the exposure period

REMOVAL OF TEST SUBSTANCE
- Washing (if done): any residual test material was removed by gentle swabbing with cotton wool soaked in distilled water
- Time after start of exposure: one patch at each time point (3 minutes, 1 hour, 4 hours and after application)

OBSERVATION TIME POINTS
lmmediately following removal of the patches and approximately 1, 24, 48 and 72 hours later, the test sites were examined for evidence of primary irritation and scored.

SCORING SYSTEM:
- Erythema and eschar formation and oedema formation were evaluated in the scale of severity from 0 to 4 (Table1).
- Method of calculation:
The scores for erythema and oedema at the 24 and 72-hour readings were totalled for the two test rabbits (8 values) and this total was divided by four to give the primary irritation index of the test material.
The test material was classified according to the scheme (Table 2) devised by Draize J H (1959) "Dermal Toxicity" ln: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. Association of Food and Drug Officiais of the United States, Austin, Texas, p.46-59:

If irreversible alteration of the dermal tissue is noted in any rabbit, as judged by the Study Director, which include ulceration and clear necrosis or signs of scar tissue, the test material is classified as corrosive to rabbit skin. Classification according to Draize may, therefore, not be applicable.
Irritation parameter:
erythema score
Remarks:
3-minute and 1-hour exposure
Basis:
animal #1
Time point:
other: Immediate, 1h, 28h, 52h, 72h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Remarks:
3-minute and 1-hour exposure
Basis:
animal #1
Time point:
other: Immediate, 1h, 28h, 52h, 72h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Remarks:
4-hour exposure
Basis:
animal #1
Time point:
other: Immediate, 1h, 24h, 48h, 72h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Remarks:
4-hour exposure
Basis:
animal #1
Time point:
other: Immediate, 1h, 24h, 48h, 72h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Remarks:
4-hour exposure
Basis:
animal #2
Time point:
other: Immediate, 1h, 24h, 48h, 72h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: Immediate, 24h, 48h, 72h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
3-minute and 1-hour semi-occluded applications of the test material to the intact skin of one rabbit produced no evidence of skin irritation.
A single 4-hour semi-occluded application of the test material to the intact skin of two rabbits produced no evidence of skin irritation.
Other effects:
All animals showed expected gain in bodyweight during the study (Table 2).

Table 2. lndividual Bodyweights and Bodyweight Changes

Rabbit Number and Sex

lndividual Bodyweight (kg)

 

Bodyweight Change (kg)

Day0

Day3

 

68684 Male

 

2.39

 

2.43

 

0.04

 

68696 Male

 

2.38

 

2.47

 

0.09
Interpretation of results:
GHS criteria not met
Conclusions:
The test material produced a primary irritation index of 0.0 and was classified as non-irritant to rabbit skin according to the Draize classification scheme. The test material did not meet the criteria for classification as irritant or corrosive according to EU labelling regulations (EC) No 440/2008.
Executive summary:

The study was performed to assess the irritancy potential of the 4,4'-Benzylidenedianiline following single, 3-minute, 1 and 4-hour, semi-occluded applications to the intact rabbit skin according to the OECD guideline 404 and method B4 of the Commission Regulation (EC) No. 440/2008. None of the applications to the rabbit intact skin produced any evidence of skin irritation. The test material produced a primary irritation index of 0.0 and was classified as non-irritant to rabbit skin according to the Draize classification scheme. The test material did not meet the criteria for classification as irritant or corrosive according to EU labelling regulations (EC) No 440/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 07 December 2009 to 17 December 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
24 April 2002
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
No. 440/2008
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
- Source: Sponsor's identification DATIPH
- Description: brown solid lumps
- Date received: 09 November 2009
- Storage conditions: approximately 4°C in the dark

The integrity of supplied data relating to the identity, purity and stability of the test material is the responsibility of the Sponsor.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: For the purpose of the study the test material was ground to a powder prior to application.
- The pH of the test material was determined prior to commencement of the study and found to be as follows:
Preparation: 10% w/w aqueous preparation of the test material
pH Measurement: immediately - 8.9; after 10 minutes - 9.4; after 20 minutes - 9.5
Species:
rabbit
Strain:
New Zealand White
Remarks:
Sex: Male
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories U.K. Limited, Hillcrest, Belton, Loughborough, UK
- Age at study initiation: twelve to twenty weeks old
- Weight at study initiation: 2.38 or 2.81 kg
- Housing: individual housing in suspended cages
- Diet (e.g. ad libitum): Free access throughout the study (2030 Teklad Global Rabbit diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK)
- Water (e.g. ad libitum): Free access throughout the study (2030 Teklad Global Rabbit diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK)
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light (06:00 to 18:00) and twelve hours darkness
- The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected
the purpose or integrity of the study.
Vehicle:
water
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml of the test material (approximately 67 mg)
Observation period (in vivo):
Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment, according to the numerical evaluation given in Table 2 (below), (from Draize J H (1977) "Dermal and Eye Toxicity Tests" ln: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.48 to 49).
Number of animals or in vitro replicates:
2
Details on study design:
A volume of 0.1 ml of the test material, which was found to weigh approximately 67 mg (as measured by gently compacting the required volume into an adapted syringe) was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball. The upper and lower eyelids were held together for about one second immediately after treatment, to prevent loss of the test material, and then released. The left eye remained untreated and was used for control purposes.

SCORING SYSTEM: lmmediately after administration of the test material, an assessment of the initial pain reaction was made according to the six point scale (see Table 1 below).
TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.

The numerical values corresponding to each animal, tissue and observation time were recorded. The data relating to the conjunctivae were designated by the letters A (redness), B (chemosis) and C (discharge), those relating to the iris designated by the letter D and those relating to the cornea by the letters E (degree of opacity) and F (area of cornea involved). For each tissue the score was calculated as follows:

Score for conjunctivae = (A+ B + C) x 2
Score for iris = Dx5
Score for cornea = (Ex F) x 5

Using the numerical data obtained a modified version of the system described by Kay J H and Calandra J C (1962), J. Soc. Cosmet. Chem. 13, 281-289 was used to classify the ocular irritancy potential of the test material (see Table 3 below). This was achieved by adding together the scores for the cornea, iris and conjunctivae for each time point for each rabbit. The group means of the total scores for each observation were calculated. The highest of these group means (the maximum group mean score) together with the persistence of the reactions enabled classification of the eye irritancy potential of the test material.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
80
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
80
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
10
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 1h, 24h, 48h, 72h
Score:
0
Max. score:
10
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 1h
Score:
8
Max. score:
20
Remarks on result:
probability of moderate irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24 h
Score:
4
Max. score:
20
Remarks on result:
probability of mild irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
48 h
Score:
0
Max. score:
20
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
20
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 1h
Score:
8
Max. score:
20
Remarks on result:
probability of moderate irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24 h
Score:
4
Max. score:
20
Remarks on result:
probability of mild irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
20
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
20
Remarks on result:
no indication of irritation
Irritation parameter:
overall irritation score
Basis:
animal #1
Time point:
other: 1h
Score:
8
Max. score:
110
Remarks on result:
positive indication of irritation
Irritation parameter:
overall irritation score
Basis:
animal #1
Time point:
24 h
Score:
4
Max. score:
110
Remarks on result:
positive indication of irritation
Irritation parameter:
overall irritation score
Basis:
animal #1
Time point:
48 h
Score:
0
Max. score:
110
Remarks on result:
no indication of irritation
Irritation parameter:
overall irritation score
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
110
Remarks on result:
no indication of irritation
Irritation parameter:
overall irritation score
Basis:
animal #2
Time point:
other: 1h
Score:
8
Max. score:
110
Remarks on result:
positive indication of irritation
Irritation parameter:
overall irritation score
Basis:
animal #2
Time point:
24 h
Score:
4
Max. score:
110
Remarks on result:
positive indication of irritation
Irritation parameter:
overall irritation score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
110
Remarks on result:
no indication of irritation
Irritation parameter:
overall irritation score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
110
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No corneal or iridial effects were noted during the study. Moderate conjunctival irritation was noted in the treated eyes one hour after treatment with minimal conjunctival irritation noted at the 24-hour observation. Treated eyes appeared normal at the 48-hour observation.
Other effects:
All animals showed expected gain in bodyweight during the study (see Table 4 below).

Table 4. Individual bodyweights and bodyweight changes

Rabbit Number and Sex

lndividual Bodyweight (kg)

 

Bodyweight Change (kg)

Day 0

Day 3

 

68712 Male

 

2.81

 

2.89

 

0.08

 

68730 Male

 

2.38

 

2.42

 

0.04
Interpretation of results:
GHS criteria not met
Conclusions:
The test material produced a maximum group mean score of 8.0 and was classified as a minimal irritant (Class 3 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.
The test material did not meet the criteria for classification as eye irritant according to EU labelling regulations (EC) No 440/2008.
Executive summary:

The study was performed ta assess the irritancy potential of the test material to the eye of the New Zealand White rabbit following the OECD guideline 405 and the Method B5 of (EC) No.440/2008 regulation.

A single application of the test material to the non-irrigated eye of two rabbits produced moderate conjunctival irritation. Treated eyes appeared normal at the 48-hour observation. The test material produced a maximum group mean score of 8.0 and was classified as a minimal irritant (Class 3 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system. The test material did not meet the criteria for classification as eye irritant according to EU labelling regulations (EC) No 440/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Justification for classification or non-classification

The test item is not classified for skin and eye irritation according to CLP criteria.